Effect and mechanism of fluoxetine on improving working memory in rats with chronic cerebral ischemia
10.3969/j.issn.1672-5921.2020.06.007
- Author:
Xiao MIN
1
Author Information
1. Department of Neurology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology
- Publication Type:Journal Article
- Keywords:
Brain ischemia;
Fluoxetine;
G protein-coupled inwardly-rectifying potassium channels;
Memory;
Short-term
- From:
Chinese Journal of Cerebrovascular Diseases
2020;17(6):320-326
- CountryChina
- Language:Chinese
-
Abstract:
Objective To observe the protective effects of fluoxetine on working memory impairment induced by chronic cerebral ischemia and further explore its mechanism in rats. Methods The rat model of chronic cerebral ischemia was made by surgical ligation of the bilateral carotid artery. 44 male Sprague Dawley rats were divided into sham group (n = 10) , ischemic model group (ra = 12), ischemic + fluoxetine group (n = 12) , and sham + fluoxetine group (n = 10). Fluoxetine was administered by gavage after 1 week of ischemic surgery and continued for 4 weeks. The sham group and the ischemic model group were given the same volume of 0. 9% saline. The performance of working memory was tested by a modified Morris water maze experiment that lasted for 4 days. The expression of neuronal nuclei (NeuN) , S-100(3, G protein gated inwardly rectifying K channels 1,2, and 3 ( GirKl , 2 , and 3 ) , and sorting nexin 27 ( SNX27 ) in the prefrontal cortex ( PFC) of rats were tested by Western blot, and compare between groups. Results (1) There was no significant difference in swimming speed among the four groups ( P > 0.05 ). In the training experiment, there was no significant difference among the four groups in the escape latency and the swimming distance ( both P > 0.05 ). In the memory retention test, the escape latency of rats in the ischemic model group was significantly increased on 2nd, 3rd and 4th day compared with the sham group (day2: [48.2 ±6. 3] s vs. [27.4±4.0]s, day 3 :[53.9 ±6.4] s vs. [29.4±6.3]s, day4: [41.4± 4. 9] s vs. [23.8 ±3.7] s; all P <0.05). The escape latency of rats in the ischemia + fluoxetine group on 3rd and 4th day was decreased compared with the ischemia model group ([31. 0 ± 6. 6]s, [26. 2 ± 3.7] s, respectively; both P<0.05). In the memory retention test, the swimming distance of rats in the ischemic group was significantly increased on 2nd, 3rd and 4th compared with the sham operation group (day 2: [553 ±76] cm vs. [313 ±51] cm, day 3: [619 ±81] cmis. [329 ±65] cm, day4: [433 ± 48] cm vs. [282 ±47] cm; all P<0.05). The swimming distance in the ischemic + fluoxetine group on 2nd, 3rd and 4th day was decreased compared with the ischemic group([373 ±54] cm, [321 ±70] cm, and [279 ±44] cm, respectively; all P<0.05). (2) There was no statistically significant difference in the expression of NeuN and S-100J3 among four groups of rats (both P >0.05). (3) There was no significant difference in the membrane expression of GirKl protein among the four groups (P > 0. 05). Taking the sham group as a reference and the relative grey value of GirK2 and GirK3 is defined as 1, the relative grey values of GirK2 in the ischemia model group and the ischemia + fluoxetine group were 1. 27 ± 0. 07 and 1. 06 ±0.06, the relative grey values of GirK3 in the ischemia model group and the ischemia + fluoxetine group were 1.23 ±0.08 and 1.00 ±0.06. The membrane expression of GirK2 and GirK3 in the ischemic model group was higher than that in the sham group. The membrane expression of GirK2 and GirK3 in the ischemic + fluoxetine group was down-regulated compared with the ischemic model group ( both P < 0. 05). (4) Taking the sham group as a reference and the relative grey value of SNX27 in the sham group is defined as 1, the relative grey values of SNX27 in the ischemia model group, the ischemia + fluoxetine group, and the sham + fluoxetine group were 0. 78 ± 0.09, 0.97 ± 0.04, and 0. 94 ±0.05, respectively. The expression of SNX27 in the ischemic model group was lower than that in the sham group, and the down-regulation of SNX27 expression in the ischemic model group was reversed after fluoxetine treatment (P<0. 05). Conclusion Fluoxetine can ameliorate working memory impairment of rats induced by chronic cerebral ischemia, which may partly reverse the increase of surface expression of GirK2 and GirK3 in the prefrontal cortex through acting on SNX27.
